Shikonin inhibits adipogenesis by modulation of the WNT/beta-catenin pathway

Abstract

Aim: Our previous study showed for the first time that shikonin, a natural compound isolated from Lithospermun erythrorhizon Sieb. Et Zucc, inhibits adipogenesis and fat accumulation. This study was conducted to investigate the molecular mechanism of the anti-adipogenic effects of shikonin. Main methods: Gene knockdown experiments using small interfering RNA (siRNA) transfection were conducted to elucidate the crucial role of beta-catenin in the anti-adipogenic effects of shikonin. Key findings: Shikonin prevented the down-regulation of beta-catenin and increased the level of its transcriptional product, cyclin D1, during adipogenesis of 3T3-L1 cells, preadipocytes originally derived from mouse embryo. beta-catenin was a crucial mediator of the anti-adipogenic effects of shikonin, as determined by siRNA-mediated knockdown. Shikonin-induced reductions of the major transcription factors of adipogenesis including peroxisome proliferator-activated receptor gamma and CCAAT/enhancer binding protein alpha, and lipid metabolizing enzymes including fatty acid binding protein 4 and lipoprotein lipase, as well as intracellular fat accumulation, were all significantly recovered by siRNA-mediated knockdown of beta-catenin. Among the genes located in the WNT/beta-catenin pathway, the levels of WNT10B and DVL2 were significantly up-regulated, whereas the level of AXIN was down-regulated by shikonin treatment. Significance: This study clearly shows that shikonin inhibits adipogenesis by the modulation of WNT/beta-catenin pathway in vitro, and also suggests that WNT/beta-catenin pathway can be used as a therapeutic target for obesity and related diseases using a natural compound like shikonin, even though the in vivo effects of shikonin and its clinical significance remain to be elucidated. (C) 2010 Elsevier Inc. All rights reserved.